INTRODUCTION

The field of Pediatric Obesity continues to rapidly evolve. In this review, we highlight the most significant developments in the past 2 years with the aim to discuss those that directly impact the clinical management of obesity in childhood and adolescence. The backdrop for this discussion is the continuing increase in the prevalence of children with obesity. The childhood obesity rate has more than tripled over the past 30 years, with obesity affecting one-fifth of children and adolescents ages 2–19 years in the United States. In fact, pediatric overweight and obesity now affect more than 30 percent of children, and it is the most common chronic disease of childhood [1]. These alarming trends demonstrate the importance of having an evidence-based approach for the management of children with obesity [2,3▪]. We review studies on the impact of the COVID-19 pandemic, addition of two new FDA-approved antiobesity medications for use in children, expansion of genetic testing for diagnosis of rare causes of obesity and growing integration of medical and surgical management in the treatment of children with obesity. 

Box 1:

no caption available

COVID-19 AND CHILDHOOD OBESITY

The impact of the COVID-19 (SARS CoV-2 or Coronavirus) pandemic on obesity prevalence in children is of great concern. Modeling studies predicted at least a 3–4% weight gain in children during the COVID-19 pandemic. In a study released by the CDC in September 2021, it was estimated that 22% of children and adolescents had obesity in August 2021 which was increased from 19% one-year prior. Children who were a healthy weight were gaining an average of 3.4 pounds per year prior to the pandemic with an increase to 5.4 pounds per year during the pandemic. For children with obesity, the expected annual weight gain increased from 6.5 pounds to 12 pounds after the pandemic began, and from 8.8 pounds to 14.6 pounds in those with severe obesity [4,5]. During the H1N1 epidemic it was noted that obesity was a risk factor for developing disease [6]. In another study, obesity in children was associated with inadequate vaccine response to influenza virus [7]. During the COVID-19 pandemic, obesity was ranked as either the 1st, 2nd or 3rd demographic factor in children with severe disease requiring ICU admittance. If obesity was not ranked 1st, cancer or immunosuppression were more prevalent in these very ill children. A study done in New York reported that obesity was the most prevalent comorbidity in the 50 cases of children > than 2 years of age severely affected by COVID-19. In addition, obesity was associated with disease severe enough to require mechanical ventilation [8].

PEDIATRIC OBESITY ALGORITHM AND MULTIDISCPLINARY APPROACH TO OBESITY

We have detailed the guidelines and challenges to management of obesity in childhood through the Pediatric Obesity Algorithm, an evidence-based roadmap for the diagnosis and management of children with obesity [9,10]. In the Algorithm, we discuss age-specific recommendations that were developed for use by practicing clinicians with topics ranging from assessment to the diagnosis and treatment of obesity comorbidities [9,11]. Children with obesity present at all ages, starting from those who develop obesity before the age of 5, those who develop obesity in early childhood, followed by those who develop obesity in adolescence. Frequently they suffer from victimization, bullying and social isolation. There are few programs providing multidisciplinary treatment for children with obesity. A prospective study which collected data from 31 pediatric weight management programs across the United States showed that early body mass index (BMI) reduction in the first month of treatment was found to be significantly associated with greater long-term BMI reduction at 6 and 12 months (defined as a ≥ 5% BMI reduction from baseline) in adolescents with obesity [12]. However, the availability of large multidisciplinary weight management programs with comprehensive multidisciplinary intervention and tertiary care intervention is limited with large sections of the United States lacking obesity medicine specialists, in particular those with experience with pediatric obesity management. Positive weight loss results have been observed in numerous studies with younger children having a greater reduction in BMI z-score in comparison to adolescents when analyzing the effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with severe obesity [10,13]. In other studies, adolescents with the most severe obesity had the greatest reductions in BMI [14].

These findings emphasize the importance of early diagnosis and intervention as children with obesity are at higher risk for several medical conditions such as metabolic syndrome, insulin resistance, high blood pressure, and hyperlipidemia. They may develop severe insulin resistance followed by the same comorbidities seen in adults with obesity: specifically prediabetes and diabetes. For youth who develop T2DM there is at least a 50% chance that the disease will progress despite treatment [15–17]. Other comorbidities often exacerbate the disease of obesity: hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, premature puberty, irregular menstruation and polycystic ovary syndrome (PCOS) and orthopedic conditions such as SCFE and Blount's disease [11]. Furthermore, children with obesity are more likely to become adults with obesity, with development of associated health problems including type 2 diabetes, stroke, and ischemic heart disease later in life. Children with a BMI percentile at the >95th percentile have a greater chance of maintaining obesity into adulthood [10,18].

NEW PHARMACOTHERAPY OPTIONS

The tragedy is that many children are unable to receive medical treatment for obesity, and for those who do receive treatment, options are limited. In regards to pharmacotherapy options available, orlistat, an enteric lipase inhibitor which prevents breakdown and absorption of fat is approved for children ≥ 12 years, but is rarely used in clinical practice due to the side effect of abdominal distress and greasy stools. Phentermine is FDA approved for weight loss only for > 16 years. Topiramate has been used for seizure control in children for years and is commonly used off label for treatment in children with obesity but is not FDA approved for this use. Metformin is commonly utilized in the population of children and adolescents, although FDA approved only in children ≥10 years with T2DM. However, metformin has been prescribed by obesity medicine specialists for polycystic ovary syndrome or severe insulin resistance with or without impaired glucose tolerance, with multiple trials [19,20] showing a small amount of weight loss associated with metformin use, particularly in the first few months of medication initiation [10]. By age 17 or 18, when more pharmaceutical treatment options are FDA approved, comorbidities have developed. Off label use of antiobesity medication is increasingly used but not routinely covered by insurance [21]. The lack of therapeutic options to treat children with obesity has resulted in most large outcome studies reporting only small decreases in BMI with lifestyle management. The lack of significant outcomes has contributed to the guidance from the AAP and ASMBS for bariatric surgery for those 10 and above with few limitations. Although it is important to have metabolic bariatric surgery as a treatment option, antiobesity medication is a treatment modality that could greatly improve outcomes in youth who both do and do not have the opportunity to have a surgical procedure. Although surgery is an extremely important tool, access to surgical programs is limited. For those children who do receive surgery, ongoing management, including pharmacotherapy is critical to prevent weight regain.

Fortunately, there is a recent approval of a GLP-1 receptor agonist specifically for children ages 12–17 with obesity (Fig. 1). In 2019, liraglutide was approved to treat type 2 diabetes mellitus in children ≥10 years In December 2020, the FDA approved the GLP-1 agonist liraglutide for use in adolescents for chronic weight management. This medication is approved for pediatric patients aged 12 and older who have obesity, as defined by specific BMI cut-offs for age and sex that correspond to a BMI 30 kg/m2 or higher for adults, and who weigh more than 60 kg (132 pounds). In their paper in the NEJM, Kelly et al. report a decrease in weight status as measured by the percentage of the 95th percentile of approximately 5% in patients who took Liraglutide plus lifestyle therapy for 56 weeks. Greater reductions were seen in the Liraglutide group as compared to placebo when the endpoint was a decrease in weight status of 10% or greater reduction in percentage of the 95th percentile. Eighty-two percent of patients were able to tolerate the maximal dose of 3.0 mg. [22] Other studies illustrate that the treatment of adolescents produces outcomes similar to adults [23,24]. Even more exciting is that with the approval of this medication, combination therapy is now possible with more traditional antiobesity medication. Studies must be done, but like adults with obesity, children and adolescents are likely to respond with greater degrees of weight loss with combination therapy. Semaglutide is another GLP-1 receptor agonist which is administered weekly and is currently not approved for use in adolescents for the treatment of obesity. However, the STEP-4 Teen trial is closing in March 2022 and we await the results which will likely become available sometime in the summer or fall of 2022. (https://clinicaltrials.gov/ct2/show/ NCT04102189) Obesity, if untreated will progress with predictable morbidity and mortality. This breakthrough drug, with impressive efficacy and safety in adults, may provide another needed therapy for our youth.

FIGURE 1: New medications available for treating children with obesity. Reproduced with permission from Cuda S, Censani M, O’Hara V, et al. Pediatric Obesity Algorithm Slides, presented by the Obesity Medicine Association. www.obesitymedicine.org/childhood-obesity. 2020-2022. www.obesitymedicine.org/childhood-obesity [Accessed 26 March 2022].

Setmelanotide is a melanocortin-4 (MC4R) receptor agonist developed for the treatment of obesity. In November 2020, setmelanotide was approved by the FDA for patients 6 years and older with obesity due to three rare genetic conditions: POMC deficiency, PCSK1 deficiency, and LEPR deficiency confirmed by genetic testing demonstrating variants in Proopiomelanocortin (POMC), Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1), or Leptin Receptor (LEPR) genes considered pathogenic, likely pathogenic, or of uncertain significance [25]. It is also in clinical trials for other rare genetic disorders associated with obesity. These disorders include Bardet-Biedl Syndrome, Alstrom Syndrome, POMC and other MC4R pathway heterozygous deficiency obesity, and POMC epigenetic disorders [26▪].

GENETIC TESTING

The practice of obesity medicine in youth has been impacted by wider availability of genetic screening for rare genetic causes of obesity (Fig. 2). Most of the testing is based on mutations in genes involved in the MC4R pathway which modulates regulation of appetite at the level of the paraventricular and arcuate nucleus of the hypothalamus. Rare genetic causes of obesity may not be all that rare for long. Testing has uncovered additional mutations in the MC4R pathway. Clinical implications are in discovery, complicated by the various kinds of mutations that can occur and the varied intra- and inter-familial phenotypical presentations of like mutations. Characteristic diagnostic complications may not develop until the 2nd or 3rd decades of life which makes earlier diagnosis even more challenging.

FIGURE 2: Rare genetic variants of obesity. Reproduced with permission from Cuda S, Censani M, O’Hara V, et al. Pediatric Obesity Algorithm Slides, presented by the Obesity Medicine Association. www.obesitymedicine.org/childhood-obesity. 2020-2022. www.obesitymedicine.org/childhood-obesity [Accessed 26 March 2022].

Currently, there at least 10 different laboratories offering genetic testing. Tests performed range from 2 to 79 different genetic mutations associated with individuals at risk for obesity. Some testing is offered free of charge to the patient and if the patient has a suspect mutation, family members may also be offered testing for free. Indications for testing are broad, but the underlying clinical suspicion is in those who present with obesity at younger than 5 years of age, defined as the criteria for early onset obesity. Clinical differentiation of children with genetic mutations associated with obesity from children in the general population can be challenging. However, children with genetic causes of obesity frequently present with severe hyperphagia, defined as an obsession and almost complete preoccupation with food [18]. Older children and adults who present with a history of childhood obesity may also meet criteria for screening. As discussed above, a new pharmacological agent, setmelanotide, is approved for use in children with specific genetic mutations. In addition, there are ongoing clinical trials for those with other mutations in the MC4R pathway as well as those with a deletion on chromosome 16p11.2. The purpose of the clinical trials is to investigate the efficacy of Setmelanotide in individuals with various heterozygous genetic mutations in the MC4R pathway. (https://clinicaltrials.gov/ct2/show/NCT04963231)

In addition to the hope of treatment with a new pharmacotherapeutic agent that may help individuals with genetic mutations, patients also benefit from increased knowledge about their condition and reduced social stigma. And, although the AMA recognized obesity as a disease in 2013, many healthcare providers still approach obesity as a lifestyle decision, but recognition of underlying genetic etiologies may help change this mindset (Fig. 2).

METABOLIC AND BARIATRIC SURGERY

Two publications have provided guidance for metabolic and bariatric surgery in youth [27,28]. Briefly, the papers use the definition of youth as 10 years of age and above. They outline the criteria for surgery: a BMI ≥ 120 percentage of the 95th percentile with a major comorbidity or > 140 percentage of the 95th percentile. The authors of these publications state that previous barriers to surgery are not supported by evidence and that clinical decision-making should govern the decision for surgery. This guidance is a major departure from previous guidance in that it removes many barriers to surgery. According to guidance from the publications, no preoperative attempt at diet or exercise is necessary, a diagnosis of autism, developmental delay or syndromal obesity is not a contraindication, and unstable family environments, eating disorders, mental illness or prior trauma are not reasons to exclude surgery [28]. In addition, these publications discuss the lack of evidence to support delaying surgery to later stages of pubertal development. A recent study by Ogle, Dewberry, Jenkins et al. examined 5-year outcomes of patients who underwent bariatric surgery from two cohorts: younger (age 13–15 years) and older (age 16–19 years). They found few differences in outcome in these two cohorts, to include percentage weight loss after 5 years, improvement or resolution of hypertension, type 2 diabetes, dyslipidemia, nutritional abnormalities and quality of life [29▪].

The most common procedure practiced is the laparoscopic gastric sleeve. Outcomes seen are similar to those in adults. It is a safe and effective procedure in most youth. Health-related quality of life metrics are dramatically improved [30] and five-year outcomes have also been positive (Fig. 3). In the 5 year Teen Labs Study, there was 96% follow-up at 5 years with a mean percentage weight loss of 26%. In regards to comorbidities, 68% normalized blood pressure, and 81% normalized triglycerides, with 86% of patients with T2DM in remission [31].

FIGURE 3: Adolescent Metabolic & Bariatric Surgery. Reproduced with permission from Cuda S, Censani M, O’Hara V, et al. Pediatric Obesity Algorithm Slides, presented by the Obesity Medicine Association. www.obesitymedicine.org/childhood-obesity. 2020-2022. www.obesitymedicine.org/childhood-obesity [Accessed 26 March 2022].CONCLUSION

More therapeutic options have become available for the treatment of youth with obesity over the last few years. We now have two FDA-approved medications for treatment, although one is currently targeted to specific genetic mutations. Genetic screening is helping to identify individuals whose obesity is clearly the consequence of a neuroendocrinological disruption. It is becoming evident that we are only beginning to understand the genetic problems associated with obesity. More identification of genetic mutations is helping reduce the stigma of obesity as a failure to exercise control over consumption and may inform healthcare providers and their patients as to which patients are at particular risk. Lastly, metabolic and bariatric surgery is becoming more available to youth with severe obesity. It can result in significant weight loss and resolve existing co-morbidities such as type 2 diabetes. In addition, long-term follow-up 5 years after surgery is showing favorable outcomes. Earlier and more comprehensive management options will provide healthcare practitioners with an evidence-based approach for the diagnosis and treatment of children with obesity, and provide patients with the tools needed for a healthy future.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

S.C. is on the Rhythm Pharmaceuticals Gold Panel and is an Advisory Board member for Novo Nordisk. She has received Honorarium from Novo Nordisk and Speakers Fees from Rhythm Pharmaceuticals. M.C. has no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015–2016. NCHS Data Brief 2017; 288:1–8. 2. Dubnov-Raz G, Maor S, Ziv-Baran T. Pediatric obesity and body weight following the COVID-19 pandemic. Child Care Health Dev 2021; 1–5. 3▪. Nogueira-de-Almeida CA, Del Ciampo LA, Ferraz IS, et al. COVID-19 and obesity in childhood and adolescence: a clinical review. J Pediatr 2020; 96:546–558. 4. Lange SJ, Kompaniyets L, Freedman DS, et al. Longitudinal trends in body mass index before and during the COVID-19 pandemic among persons aged 2-19 years – United States, 2018–2020. MMWR Morb Mortal Wkly Rep 2021; 70:1278–1283. 5. Stavridou A, Kapsali E, Panagouli E, et al. Obesity in children and adolescents during COVID-19 pandemic. Children 2021; 8:1–16. 6. Diaz E, Rodriguez A, Martin-Loeches I, et al. Impact of obesity in patients infected with 2009 influenza A(H1N1). Chest 2011; 139:382–386. 7. Green WD, Beck MA. Obesity impairs the adaptive immune response to influenza virus. Ann Am Thorac Soc 2017; 14: (Supplement_5): S406–S409. 8. Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients with coronavirus disease 2019 (COVID-19) in a Children's Hospital in New York City, New York. JAMA Pediatr 2020; 174:e202430. 9. Cuda SE, Censani M, O’Hara V, et al. Pediatric Obesity Algorithm 2020–2022 [Available from: Available online at: www.Pediatricobesityalgorithm.org. 10. Cuda S, Censani M. Diabetes and Obesity in the Child and Adolescent: Guidelines and Challenges. In: Faintuch, J., Faintuch, S., editors. Obesity and Diabetes: Springer, Cham 2020; pp. 553-566. 11. Cuda SE, Censani M. Pediatric obesity algorithm: a practical approach to obesity diagnosis and management. Front Pediatr 2018; 6:1–14. 12. Gross AC, Kaizer AM, Kelly AS, et al. Long and short of it: early response predicts longer-term outcomes in pediatric weight management. Obesity 2019; 27:272–279. 13. Zolotarjova J, Ten Velde G, Vreugdenhil ACE. Effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with morbid obesity. Obes Rev 2018; 19:931–946. 14. Kumar S, King EC, Christison AL, et al. Health outcomes of youth in clinical pediatric weight management programs in POWER. J Pediatr 2019; 208:57–65. e4. 15. Arslanian S, Bacha F, Grey M, et al. Evaluation and management of youth-onset type 2 diabetes: a position statement by the American Diabetes Association. Diabetes Care 2018; 41:2648–2668. 16. Buse JB, D’Alessio DA, Riddle MC. Can We RISE to the challenge of youth-onset type 2 diabetes? Diabetes Care 2018; 41:1560–1562. 17. Valaiyapathi B, Gower B, Ashraf AP. Pathophysiology of Type 2 diabetes in children and adolescents. Curr Diabetes Rev 2020; 16:220–229. 18. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2017; 102:709–757. 19. Mauras N, DelGiorno C, Hossain J, et al. Metformin use in children with obesity and normal glucose tolerance--effects on cardiovascular markers and intrahepatic fat. J Pediatr Endocrinol Metab 2012; 25:33–40. 20. Kendall D, Vail A, Amin R, et al. Metformin in obese children and adolescents: the MOCA trial. J Clin Endocrinol Metab 2013; 98:322–329. 21. Srivastava G, Fox CK, Kelly AS, et al. Clinical considerations regarding the use of obesity pharmacotherapy in adolescents with obesity. Obesity 2019; 27:190–204. 22. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl J Med 2020; 382:2117–2128. 23. Kelly AS, Rudser KD, Nathan BM, et al. The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial. JAMA Pediatr 2013; 167:355–360. 24. Danne T, Biester T, Kapitzke K, et al. Liraglutide in an adolescent population with obesity: a randomized, double-blind, placebo-controlled 5-week trial to assess safety, tolerability, and pharmacokinetics of liraglutide in adolescents aged 12-17 years. J Pediatr 2017; 181:146–153. e3. 25. Markham A. Setmelanotide: first approval. Drugs 2021; 81:397–403. 26▪. Clement K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol 2020; 8:960–970. 27. Armstrong SC, Bolling CF, Michalsky MP, et al. Pediatric metabolic and bariatric surgery: evidence, barriers, and best practices. Pediatrics 2019; 144: 28. Pratt JSA, Browne A, Browne NT, et al. ASMBS pediatric metabolic and bariatric surgery guidelines. Surg Obes Relat Dis 2018; 14:882–901. 29▪. Ogle SB, Dewberry LC, Jenkins TM, et al. Outcomes of bariatric surgery in older versus younger adolescents. Pediatrics 2021; 147:e2020024182. 30. Rigal N, Bouvet C, Oderda L, et al. Mental health of adolescents after bariatric surgery: a textual analysis. Clin Obes 2021; 11:e12480. 31. Inge TH, Jenkins TM, Xanthakos SA, et al. Long-term outcomes of bariatric surgery in adolescents with severe obesity (FABS-5+): a prospective follow-up analysis. Lancet Diabetes Endocrinol 2017; 5:165–173.